Chewable oral unit dosage

ABSTRACT

An oral unit dosage comprising a substrate defining a plurality of discrete reservoirs each containing a liquid fill for release in the mouth.

This application is a 371 of PCT/GB99/01851 filed Jun. 10, 1999.

BACKGROUND OF THE INVENTION

This invention relates to chewable capsules having improvedacceptability for the consumer.

Soft gelatin capsules are a well established means for providing avariety of liquid products such as drugs or dietary supplements in arelatively digestible form.

EP 0211079 discloses a partitioned soft capsule in which a rapidlysoluble film is used to form both parts of a capsule. The capsule isable to deliver two separate liquid compositions which are containedwithin separate but adjacent reservoirs in the capsule to the mouth. Thecapsules of this patent suffer the disadvantage that they are not easyto grip between the teeth when chewing and are thus prone to “poppingout” from between the teeth as the patient bites the capsule. Inaddition, it is necessary to form the capsule from at least threeseparately fed sheets of material thereby increasing the complexity ofmanufacture and hence the cost per capsule.

When chewable capsules are chewed or bitten (rather than swallowed),they release their contents into the mouth. This may be particularlyadvantageous when the capsule contents have a topical effect in themouth or throat or when the liquid fill provides a soothing or coatingeffect. Delivering liquids by this means is particularly useful whenbulk doses of liquid medicaments are not convenient (e.g. because offrequent or irregular dosing patterns or when measuring doses accuratelyis not convenient).

Chewable capsules may also be particularly advantageous when the patientis unable or unwilling to swallow solid dosage forms (e.g. tablets orhard capsules) e.g. because of age, throat pain/constriction etc.

The full commercial development of such chewable dosage forms hashowever been hindered by two particular drawbacks.

Firstly, for capsules above a volume of approximately 0.5 ml, when thecapsule is bitten the resulting burst of contents is aestheticallyunpleasant, indeed it has been likened to “biting an eyeball”. Toovercome this drawback it has been suggested that the fill volume of thecapsules should be reduced, but this is not always practical. To reducethe fill volume whilst delivering the same drug dosage the fill must bemore concentrated, which in most cases means more viscous. Increasingviscosity leads to difficulty in filling the capsules accurately (as thefill must be pumped through narrow dosing tubes) and consequentunacceptable dose variations. Also small capsules are difficult tolocate between the teeth and are therefore difficult to break open.

A second disadvantage of conventional chewable capsules is that manyactive materials or excipients are incompatible with each other whencombined in a liquid fill. This incompatibility may be due to reactionsbetween two or more components of the liquid fill, leading to e.g.degradation of one or more of the active materials, or the release ofgases which cause the capsules to burst. This means that for manycombinations of active, materials and or excipients it is necessary toprovide two or more different capsules each time a dose is taken;increasing the risk of confusion of the patient and poor compliance withthe correct dosing schedule.

There is thus a need for a chewable capsule which is capable ofdelivering one or more liquid compositions to the mouth without theunpleasant sensation of the contents spurting out that occurs when aconventional capsule is bitten. It is also desirable for the chewablecapsule to be suitable for delivering two or more incompatible liquidformulations to the patient via a single oral dosage form. Ideally, thechewable capsules should have a simple construction and be inexpensiveto manufacture. The present invention aims to provide a chewable capsulesatisfying the above aims and having a mouth feel which is acceptable tothe patient.

SUMMARY OF THE INVENTION

According to the present invention there is provided a chewable oralunit dosage for releasing liquid in the mouth, comprising a softingestible substrate which includes a plurality of spatially-separatedreservoirs, wherein each reservoir is adapted to retain liquid fills,preferably discrete liquid fills, and wherein the release of the liquidfills from the reservoirs occurs in a controlled manner when he unitdosage is chewed.

Preferably the oral unit dosage is a capsule, more preferably a gelatincapsule.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of an oral unit dosage according to the invention.

FIG. 2 is a side view cross section (A—A) of an oral unit dosageaccording to the invention.

FIG. 3 is an end view cross section (B—B) of an oral unit dosageaccording to the invention.

By controlled manner it is meant that, whether or not more than oneliquid fill composition is used in the same capsule, the normal liquidfill volume is divided between a number of smaller reservoirs with theresult that only a few reservoirs are burst in any one bite and thesudden burst of a large volume of liquid fill will be avoided.

The individual discrete reservoirs are non interconnecting and arespaced apart from one another.

Preferably in the oral unit dosages of the invention each reservoir hassubstantially the same volume.

Preferably the volume of each of the reservoirs in the oral unit dosagesof the invention is not more than 0.5 ml, more preferably it is from0.05 to 0.5 ml and most preferably from 0.1 to 0.35 ml.

Preferably the substrate of the oral unit dosages or the inventioncomprise from 2 to 30 reservoirs, more preferably from 5 to 20, and mostpreferably from 10 to 15.

Optionally the oral unit dosages of the invention may contain at leasttwo different liquid fills in different reservoirs. The different liquidfills may separately contain components that would be incompatible ifthey were combined in a single liquid fill, for example two incompatibleactive materials or an active material and an incompatible excipient.

Examples of incompatible components include acids and bases; for examplealginic acid and sodium bicarbonate, cetylpyridinium chloride andascorbic acid, cimetidine and sodium bicarbonate, effervescent couples(e.g. citric acid and sodium bicarbonate), aspartame (a sweetener) andmagnesium trisilicate (an antacid), cimetidine and vanilla (a flavouringagent), or benzocaine and cherry flavour.

It is possible in the oral unit dosages of the invention that the wallsof the reservoirs are composed of a different material from thesubstrate in which they are embedded. However, it is preferred that thereservoir walls are composed of the same material as the substrate, i.e.the reservoirs are merely spaces in the substrate produced by theinsertion of and/or including the liquid fill(s).

Thus, the oral unit dosages of the invention preferably consistessentially only of two components, the substrate and one or more liquidfills plus, optionally, a coating agent.

The substrate may comprise any film-forming material suitable forforming chewable capsules, for example suitably treated starch,cellulose or derivatives thereof or gelatin. Preferably the substratecomprises gelatin.

The substrate may further comprise agents to improve its handling ororganoleptic properties, for example plasticisers (e.g. glycerine,sorbitol or propylene glycol, in amounts of up to 50%, more preferably20-35%, by weight of the substrate); water (up to 50%, more preferably30-40%, by weight of the substrate); preservatives (e.g. potassiumsorbate or methyl, ethyl or propyl parabens); dyes; opacifiers;flavours; or additional drug substances.

The liquid fill will comprise either a solid active material that hasbeen dissolved, solubilised, or dispersed (with suspending agents suchas beeswax, hydrogenated caster oil or polyethylene glycol 4000), or aliquid active material; in vehicles or combinations of vehicles such asmineral oil, vegetable oils, triglycerides, glycols, polyols, andsurface active agents.

The liquid fill may optionally also comprise flavouring agents,sweeteners or powdery materials to improve the mouth feel of the fillonce the reservoirs are broken open (e.g. bulk sweeteners such assucrose or mannitol).

The selection of appropriate substrate materials plus excipients andfill materials will be obvious to one skilled in the art of chewablecapsule production, and will depend largely upon the active materialbeing delivered by the oral unit dosage of the invention.

It will be appreciated that, when the amount of fill material dosed intoeach reservoir is fairly low, care should be taken to ensure that thefill is not too viscous for accurate dosing. This will not be such aproblem as in the production of single low volume capsules as theconcentration of active agent will not need to be so high as in suchcapsules.

Suitable active materials for use in the oral unit dosages of theinvention include any materials that may be formulated in a liquid fill,for example:

a) systemically acting agents, such as histamine H₂ receptor antagonists(e.g. ranitidine), proton pump inhibitors (e.g. omeprazole), prokineticagents (e.g. metoclopramide), antidiarrhoeal agents (e.g. loperamide),laxatives (e.g. senna powder), non seroidal anti-inflammatory agents(e.g. naproxen, diclofenac, ibuprofen and aspirin) or decongestants(e.g. pseudoephedrine);

b) materials acting locally in the mouth, such as local antimicrobialagents (e.g. cetyl pyridinium chloride, hexyl resorcinol, triclosan),local anaesthetics (e.g. lignocaine hydrochloride, benzocaine)anti-inflammatory agents (e.g. aspirin, benzydamine, ketoprofen)steroids (e.g. hydrocortisone), topical antibiotics (e.g. tyrothricin,fusafungine, nystatin), decongestants (e.g. phenylephrine hydrochloride)or antihistamines (e.g. terfenadine);

c) materials acting locally in the throat or oesophagus, such as coughsuppressants (e.g. dextromethorphan), expectorants (e.g. guiaphenesin),antacids (e.g. calcium carbonate, sodium bicarbonate), orsoothing/coating agents (e.g. sodium alginate or dimethicone.

Suitable materials that may optionally be used to coat the oral unitdosages of the invention include cellulose derivatives such as hydroxyethyl cellulose, hydroxy methyl cellulose or hydroxy propyl cellulose.

The oral unit dosages of the invention may be manufactured by any of themethods normally used for the production of chewable capsules having lowfill volumes (taking into account the materials selected), with thespecial adaptation that the encapsulated dosages are not separatedindividually but are divided up so that each dosage comprises aplurality of discrete reservoirs. The method of manufacture may befurther adapted so that each of the individual reservoirs has a volumeof less than 0.5 ml and/or so that two or more different liquid fillsare included in different reservoirs within the same oral unit dosage.

Commercial methods for producing chewable capsules include the plateprocess and the rotary die encapsulation process.

Example of the use of both the plate process and rotary dieencapsulation machines are give in, for example, Soft Gelatin Capsules:A Solution To Many Tableting Problems by H. Seager in PharmaceuticalTechnology, September 1985, 84-104; and Soft Gelatin Capsules by J. P.Stanley in Theory and Practice of Industrial Pharmacy Eds Lachman L,Lieberman H A, Konig J L, 405-420, 1976.

The invention will now be described with reference to the drawings inwhich:

In the Figures, the oral unit dosage 10 includes a flat gelatin laminate12 consisting of two separate gelatin cards 12A and 12B laminatedtogether. The gelatin laminate 12 includes six discrete, sealed,reservoirs 14 which are non-interconnecting and are spaced apart fromone another. Each reservoir 14 is filled with liquid fill 16.

When the unit dosage is chewed, only a few reservoirs will burstyielding their liquid fill in any one bite with the result that a suddenburst of a large volume of liquid fill is avoided.

The invention will now be illustrated by reference to the followingexamples:

EXAMPLE 1

Liquid Fill mg Per Capsule Calcium Carbonate 500 Sodium Bicarbonate 100Fractionated Coconut Oil 600 Lecithin 12 Colloidal Silicon Dioxide 34Sorbitan Fatty Esters 34 Polysorbate 80 BP 20Flavours/Colours/Sweeteners 80 1380 mg (1.2 ml)

Capsule Material % by Weight Gelatin 40 Glycerin 25 Water 35 MintFlavour qs Sweetener qs Colour qs

The oral unit dosages are prepared on a conventional rotary dieencapsulation machine adapted to provide an individual fill volume of0.1 ml; and further adapted so that the encapsulated reservoirs are notindividually cut off but are divided up in blocks of 12 reservoirs i.e.each oral unit dosage comprises a single piece of gelatin definingtwelve reservoirs each having a liquid fill of 0.1 ml.

The resultant chewable capsules deliver an antacid material to thethroat and oesophagus without the “chalky” characteristics normallyassociated with conventional antacid tablets. The capsules are pleasantto chew and do not produce an unpleasant burst effect upon biting.

EXAMPLE 2

Liquid Fill 1 mg per capsule Calcium carbonate 100 Sodium bicarbonate100 Lecithin 12 Fractionated coconut oil 600 Colloidal silicon dioxide34 Sorbitan fatty ester 34 Poly sorbate 80 20Flavours/Colours/Sweeteners 80 1380 mg (1.2 ml)

Liquid Fill 2 mg per capsule Alginic acid 500 Lecithin 12 Fractionatedcoconut oil 600 Colloidal silicon dioxide 34 Sorbitan fatty esters 34Polysorbate 80 20 Flavours/Colours/Sweeteners 80 1380 mg (1.2 ml)

Capsule Material

As example 1

The oral unit dosages are prepared as in Example 1 with the furtheradaptation that the two liquid fills are delivered separately to thecapsules, such that each oral unit dosage comprises a single piece ofgelatin defining twelve reservoirs each of 0.1 ml volume, six of thereservoirs containing liquid fills and six containing liquid fill 2.

Two capsules of Example 2 provide a full dose of alginic acid which willform a raft on contact with the stomach contents to treat heartburn,gastritis or dyspepsia.

When chewed the capsules of example 2 have a pleasant mouth feel and donot give a sudden unpleasant burst of fill material.

What is claimed is:
 1. A chewable oral unit dosage for releasing liquidin the mouth, said dosage comprising a soft ingestible substrate whichcomprises from 2 to 30 spatially-separated reservoirs, wherein eachreservoir has a volume of not more than 0.5 ml and contains a liquidfill and wherein release of the liquid fill from the reservoirs occursin a controlled manner when the unit dosage is chewed.
 2. An oral unitdosage according to claim 1 wherein the plurality of reservoirs contain2 or more different liquid fills.
 3. An oral unit dosage form accordingto claim 1 wherein the volume of each reservoir ranges from 0.05 to 0.5ml.
 4. An oral unit dosage according to claim 3 wherein the volume ofeach reservoir ranges from 0.1 to 0.35 ml.
 5. An oral unit dosageaccording to claim 1 wherein the substrate comprises from 5 to 20reservoirs.
 6. An oral unit dosage according to claim 5 wherein thesubstrate comprises from 10 to 15 reservoirs.
 7. An oral unit dosageaccording to claim 1 wherein the substrate comprises an ingestiblefilm-forming material.
 8. An oral unit dosage according to claim 7wherein the reservoir walls are composed of the same material as thesubstrate.
 9. An oral unit dosage according to claim 7 wherein thefilm-forming material is gelatin.
 10. An oral unit dosage according toclaim 1 wherein the liquid fill composition comprises one or more activeagents selected from the group consisting of systemically active agents,materials acting locally in the mouth and materials acting locally inthe throat or oesophagus.
 11. An oral unit dosage according to claim 10wherein the liquid fill composition comprises a systemically activeagent selected from the group consisting of histamine H₂ receptorantagonists, proton pump inhibitors, prokinetic agents, antidiarrhoealagents, laxatives, non-steroidal anti-inflammatory agents, decongestantsand pharmaceutically compatible mixtures thereof.
 12. An oral unitdosage according to claim 11 in which the systemically active agents areselected from the group consisting of ranitidine, omeprazole,metoclopramide, loperamide, senna powder, naproxen, diclofenac,ibuprofen, aspirin, pseudoephedrine and pharmactically compatiblemixtures thereof.
 13. An oral unit dosage according to claim 10 whereinthe liquid fill composition comprises materials acting locally in themouth, said materials selected from the group consisting of localantimicrobial agents, local anaesthetics, anti-inflammatory agentssteroids topical antibiotics, decongestants, anti-histamines andpharmaceutically compatible mixtures thereof.
 14. An oral unit dosageform according to claim 13 in which the materials acting locally in themouth are selected from the group consisting of cetylpyridiniumchloride, hexyl resorcinol, lignocaine hydrochloride, benzocaine,aspirin, benzydamine, ketoprofen, hydrocortisone, tyrothricin,fusafungine, nystatin, phenylephrine hydrochloride, terfenadine andpharmaceutically acceptable mixtures thereof.
 15. An oral unit dosageaccording to claim 10 wherein the liquid fill composition comprisesmaterials acting locally in the throat or oesophagus, said materialsselected from the group consisting of cough suppressants, expectorants,antacids, soothing or coating agents and pharmaceutically compatiblemixtures thereof.
 16. An oral unit dosage according to claim 13 in whichthe materials acting locally in the throat or oesophagus are selectedfrom the group consisting of dextromethorphan, guiaphenesin, calciumcarbonate, sodium bicarbonate, sodium alginate, dimethicone andpharmaceutically acceptable mixtures thereof.
 17. An oral unit dosageaccording to claim 10 wherein the substrate further comprises one ormore of plasticisers, water, preservatives, dyes, opacifiers, flavours,additional active agents and sweeteners.
 18. An oral unit dosage formaccording to claim 17 wherein the active agents in the liquid fillcompositions are dissolved, solubilised, emulsified and/or dispersed.19. An oral unit dosage according to claim 18 wherein each of thereservoirs contains calcium carbonate and sodium bicarbonate.
 20. Anoral unit dosage form according to claim 18 wherein at least one of thereservoirs contains calcium carbonate and sodium bicarbonate and atleast one of the reservoirs contains alginic acid.